7, 17beta-dioxygenated androst-4-en-3-one



United States Patent "Ice Patented Nov. 24, 1964' 3,158,6277,17p-DIOXYGENATED ANDRflST- LEN S-ONE Stephen Kraychy, Northhrooh,Ill., assignor to G. D. Searie & (30., Chicago, liL, a corporation ofDelaware No Drawing. Filed Oct. 23, 1962, Ser. No. 232,581 Claims. (6i.260-3914) This invention relates to 7,l7;8-dioxygenated androst-4-en-3-one and processes for the manufacture thereof. More particularly,this invention provides new and useful chemical compounds of the formulathe alkyl grouping called for being such as methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, neopentyl,hexyl, isohexyl, or like C,,H moiety. Alkanoyl radicals containing fewerthan 8 carbon atoms are, for the purposes of this invention, consideredlower alkanoyl radicals.

The compounds to which this invention relates are useful by reason oftheir valuable pharmacological properties. Thus, for example, they areanabolic and androgenic agents.

Manufacture of the 7-hydroxy compounds hereof proceeds by contacting anappropriate 7-hydroxyandrost-4- ene-3,17-dione (configuration of the7-hydroxyl being as desired in the final product) with sodiumborohydride in methanol solution to convert the carbonyls therein tohydroxyls, then contacting the resultant triol with finelygroundmanganese dioxide in 2-propanol. From the 7-hydroxyl compounds thusobtained the corresponding esters hereof derive on contact with anappropriate alkanoic acid anhydride in the presence of pyridine.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirmanufacture. However, the invention is not to be construed as limitedthereby, either in spirit or in scope, since it will be apparent tothose skilled in the art of organic synthesis that many modifications,both of material and of methods, may be practiced without departing fromthe purpose and intent of this disclosure. Throughout the exampleshereinafter set forth,

temperatures are given in degrees Centigrade and relative amounts ofmaterials in parts by weight, except as otherwise noted. Specificrotations refer to the D line of sodium, the compound in each instancebeing dissolved 1% in chloroform solution.

EXAMPLE 1 g A. Andr0st-4-ene-3,7a,17B-triol.--To a solution of 293 partsof '7a-hydroxyandrost-4-en-3,l7-dione in 16,000

' ground manganese dioxide.

obtained is neutralized with acetic acid and thereupon extracted withchloroform. The chloroform extract is Washed with water, dried overanhydrous sodium sulfate, and stripped of solvent by distillation. Theresidue is androst-4-ene-3,7a,l7 3-triol.

B. 7a,]7B-dihydroxyandr0st4-en-3-0ne.-To a solution of 185 parts ofandrost-4-ene-3,7a,17/3-triol (prepared as described in the foregoingPart A of this example) in 8000 parts of 2-propanol is added 2000 partsof finely- The resultant mixture is maintained with agitation at roomtemperatures overnight, then filtered. The filtrate is evaporated todryness and the residue crystallized from acetone. Recrystallizationfrom ethyl acetate affords 7u,17p-dihydroxyandrost- 4-en-3.-one meltingat 221-223 and further characterized by a specific rotation at 27 of+885 The product has the formula r EXAMPLE 2v one melting atapproximately 1885-4895 and further characterized by a specific rotationat 28 of +4.5 The product has the formula ---OCOCH;

EXAMPLE 3 A. Andr0st-4-ene-3,7fl,17fi-tri0l.-T0 a solution of 31 partsof 7 18-hydroxyandrost-4-ene-3,l7-dione in 1260 parts of methanolisslowly added, at room temperatures with agitation, a solution of 10parts of sodium borohydride in parts of methanol. The resultant solutionis allowed to stand at room temperatures overnight, then poured into10,000 parts of water. The mixture thusobtained is neutralized withacetic acid and thereupon extracted with chloroform. The chloroformextract is washed with water, dried over anhydrous sodium sulfate,.andstripped of solvent by distillation. The residue is androst-4-ene3,7,8,l7fi-triol.

B. 75,] 7B-dihydr0xyandrost-4-en-3-one.To a solution of 24 parts ofandrost-4-ene-3,17;3,l7fl-triol (prepared as described in the foregoingPart A of this example)- in 800 parts of 2-propanol is added, withagitation, 200 parts of finely-ground manganese dioxide. Theresultantmixture is maintained with agitation at-room temperaturesovernight, then filtered. The filtrate is stripped of solvent by vacuumdistillation. The .residue, consecutively recrystallized from acetoneand ethyl acetate, afiords 7fi,l7fl J 3 4 dihydroxyandrost-4-en-3-onemelting at approximately What is claimed is: 196 197? and fur'thercharacterized by a specific rotation 1. A compound selected from thegroup consisting of a at 29 of +103". The product has the formulacompound of the formula Ha OH H3O m 'OH and a compound of the formula Hon HaC EXAMPLE 47B,'1'7fi-dz'acef0xyafzdr0st-4-en-3-one.-Substitution-of 5 2 parts of718,l7B-dihydroxyandrost-4-en-3-one for the o7a,17fl-dihydroxyandrost-4-en-3-one called for in Example I 2 affords,by the procedure there detailed, 75,17,8-diwherein R is selected fromthe group consisting of hydroacetoxyandrost-4-en-3-one melting atapproximately 182- gen and lower alkanoyls. 183 and furthercharacterized by a specific rotation at 2.7a,17B-dihydroxyandrost-4-en-3-one. 28 of +895". The product has theformula 3. 7a,-17fi-diacetoxyandrost-4-en-3-one.

4. 7/3,l7Q-dihydroxyandrost-4-en-3-one.

5. 7B,l7B-diacetoxyandrost-4-en-3-one.

11,0 00 30 References Cited in the file of this patent UNITED STATESPATENTS 22,960,513 Thoma etal Nov. 15, 1960 OTHER REFERENCES Tweit etal.: I. Organic Chemistry, 1961, vol. 26, pp. 2856-2859.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA